Summary of Work: The potent receptor selective delta-opioid based on the Dmt-Tic pharmacophore underwent numerous modifications at two portions of the molecule: either direct alterations to the Tic residue or its aromatic nucleus, or changes at the C-terminus of the dipeptide. The protonated nitrogen remained either a secondary or teriary amine. All C-terminal substituents basically exhibited little effects on delta affinity except those in which the integrity of Tic was substantially disrupted. In analogues containing substituents on the Tic aromatic ring, however, the remarkable and dramatic increase in interaction toward the mu receptor yielded peptides lacking selectivity. The addition of nucleophiles to the aromatic ring of [des-COOH]Tic containing Dmt dipeptides produced a variety of peptides whose bioactivity spectrum indicated mixied delta antagonism/mu agonism or delta antagonism/mu antagonism. The data further verified that delta affinity does not require a negative charge; other factors, including the strong interaction of Dmt within the receptor appears to dominate. The crystalline structure of H-Dmt-Tic-NH-1-adamantane revealed that this peptide, which lacks delta antagonism, differed considerably from N,N(Me)2-Dmt-Tic-OH and may account for the differences in their bioactivity. The key residues required for highly active delta antagonist are Dmt and Tic; however, new Dmt di- and pseudo-tripeptides with additional aromatic centers are currently being investigated. A series of Dmt analogues lacking Tic and recently developed in collaboration with Japan may lead to new type of mu agonists to permit a possible alleviation of cancer-induced pain.